Association of endometriosis with family history of non-Hodgkin's lymphoma: presentation of 10 cases.

PURPOSE: Women with endometriosis have been reported to be at increased risk of developing non-Hodgkin's lymphoma (NHL). The purpose of this article was to investigate the familial risk of NHL in women with endometriosis. We report on 10 cases with endometriosis and positive family history of NHL. METHODS: The medical records of 405 women with endometriosis and 200 without endometriosis were retrospectively analysed. All of the cases were diagnosed by laparoscopy. Ten cases of endometriosis having first-degree relatives with NHL are reported. RESULTS: We found no case with endometriosis and NHL. In contrast, we found 10/405 (2.5%) women with endometriosis and first-degree relatives with NHL. Their mean age was 38.3 years (range 29-46). The main complaint was infertility. The mean age at onset of endometriosis was 32 years (range 22-43). The stages of endometriosis were: stage II (n=4), stage III (n=2) and stage IV (n=4). All of these patients had first-degree relatives with a history of NHL. Five had mothers with NHL, 5 had fathers and one had a sister. CONCLUSION: These cases could suggest a link between a family history of NHL and subsequent development of endometriosis in the first-generation women. Moreover, there was no evidence of association between endometriosis and NHL.

Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines.

Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis. Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis. Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease. In the present study, we investigate the soluble levels of vascular endothelial growth factor (VEGF), epidermal growth factor-receptor (EGF-R), granulocyte/macrophage-colony stimulating factor (GM-CSF), Insulin-like growth factor-1 (IGF-1) and interferon-gamma (IFN-gamma) in the serum of 28 women with and 20 without endometriosis. We also compared these levels before, during and after treatment with danazol and leuprorelin acetate depot, the two therapeutic regiments of choice concerning this disease. We found that only sVEGF levels were higher in women with endometriosis in comparison to controls (P < 0.001) while sEGF-R is not present. GM-CSF, IGF-1 and IFN-gamma soluble levels are not affected in either healthy or endometriotic subjects. The 6-month treatment with danazol decreased sVEGF levels (P < 0.02) and increased sEGF-R levels (P < 0.001). These observations support the view that VEGF may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold. However, future studies will be focused on the anti-angiogenic control of the action of VEGF in patients with endometriosis.

Down-regulation of liver iron-regulatory protein 1 in haemochromatosis.

Cellular iron homoeostasis is maintained by iron sensor proteins known as iron-regulatory proteins (IRPs), which act post-transcriptionally by binding RNA stem-loop structures, termed iron-responsive elements (IREs), present on the mRNAs of proteins involved in iron storage, utilization and transport. IRP1 is a bifunctional protein that can act either as a cytoplasmic aconitase or as an IRE-binding protein. The RNA-binding activity of IRP1 is regulated post-translationally by the insertion or extrusion of a 4Fe-4S cluster, without changes in the levels of protein. In hereditary haemochromatosis (HH) accumulation of iron in parenchymal tissues, including the liver, occurs, possibly through dysfunctional IRP1. Investigation of IRP1 expression in liver biopsies from HH patients showed that the protein is completely absent or markedly reduced in heavily iron-loaded HH patients. Real-time PCR was then conducted in an attempt to investigate the mRNA levels and establish the underlying mechanism behind the disappearing act of IRP1. The two possibilities are: transcriptional regulation (through the inhibition of transcription) or post-transcriptional regulation (either through increased turnover of protein or inhibition of translation) of IRP1. Preliminary data suggest that transcription of IRP1 is not affected by chronic iron overload, and down-regulation may be attributable instead to degradation of the protein.

Detection of interleukin-6, interleukin-8, and interleukin-11 in plasma from women with spontaneous abortion.

OBJECTIVE: To investigate the role of IL-6, IL-8, and IL-11 in the immune-regulatory mechanisms involved in the spontaneous abortion of the first trimester of pregnancy. STUDY DESIGN: Plasma levels of IL-6, IL-8, and IL-11 were determined in 68 women who had a spontaneous abortion of unknown aetiology during the first trimester of pregnancy. They were compared with the corresponding levels of 73 age-matched pregnant women who had an uneventful pregnancy, and 52 age-matched non-pregnant women. All enrolled women presented without any severe disease, syndrome or recent infection. Cytokine levels were measured by a sensitive sandwich enzyme-linked immunoassay. RESULTS: The women with spontaneous abortion had significantly decreased plasma levels of IL-6, IL-8 and IL-11 compared to those with normal pregnancies (P<0.05). The non-pregnant women had no detectable cytokine levels. CONCLUSIONS: The reduced plasma levels of IL-6, IL-8 and IL-11 in women with spontaneous abortion may be related to the underlying aetiopathogenetic mechanisms, however, there is no sufficient evidence for their use as predictive markers of pregnancy outcome.

Soluble ICAM-1 levels in the serum of endometriotic patients appear to be independent of medical treatment.

Adhesion molecules regulate the interaction of cells with the extracellular matrix and/or other cells. The intercellular adhesion molecule-1 (ICAM-1; CD54) is a member of the immunoglobulin superfamily and expressed by several cell types, including leukocytes and endothelial cells. A circulating form of the usually membrane-bound molecule was identified and characterized in normal human serum and in sera from patients with endometriosis. In the present study, we established the serum-soluble ICAM-1 (sICAM-1) levels in patients with endometriosis. We also studied the effect of danazol and leuprorelin acetate depot on the levels of sICAM-1. Thirty-eight women, 18-45 years of age, with regular menses and documented pelvic endometriosis were recruited from a University Hospital setting. Twenty-two women with endometriosis were randomly divided into two groups. Danazol (600 mg) were given every day for 6 months, and 3.75 mg of leuprorelin acetate depot every 28 days for 6 months. Serum sICAM-1 concentrations were measured before, during and after treatment, and its quantitative determination was performed by an ELISA technique using a specific immunoassay. We found that (1) sICAM-1 levels were higher in women with endometriosis in comparison to healthy subjects; (2) the 6 month treatment with danazol or leuprorelin acetate depot increased sICAM-1 levels (P<0.001); (3) 3 months after termination of both treatments, sICAM-1 levels were unchanged. Although the mechanism leading to the increase of sICAM-1 needs to be further clarified, any benefits of medical treatment of endometriosis such as danazol or leuprorelin appear to be independent of changes in ICAM-1 serum levels.

The possible anti-inflammatory role of circulating human leukocyte antigen levels in women with endometriosis after treatment with danazol and leuprorelin acetate depot.

BACKGROUND: Endometriosis is defined as an inflammatory condition of the female reproductive tract, a state often associated with infertility and miscarriage. Many exogenously administered factors (treatments) control the disease via as yet unknown pathways. Possible candidate molecules involved in these mechanisms could be the serum-soluble human leukocyte antigens (sHIA) that have been detected in a variety of human body fluids and that are associated with several diseases. AIMS: We here examine how danazol and leuprorelin acetate depot treatments exert their anti-inflammatory action. It is plausible that subtle alterations mediated by these treatments and in relation to sHLA may explain the pathophysiology of endometriosis and provide insights towards new therapeutic protocols. METHODS: Indirect enzyme-linked immunosorbent assay (ELISA), using specific monoclonal antibodies, determined serum-soluble class-I and class-II HLA levels. ELISA readings from treated women were compared with normal healthy subjects. RESULTS: Serum-soluble class-I and class-II HLA levels are statistically significantly lower (P < 0.001) in women with endometriosis than in the control groups. However, danazol but not leuprorelin acetate depot administration augments soluble HLA class I and class II (P < 0.01 and P < 0.001, respectively) to normal levels during the treatment period, an increase that may account for the anti-inflammatory effect and the remission observed. CONCLUSIONS: It is shown that one of the underlying causes of endometriosis may be the lack of both circulating class-I and class-II antigen levels. Danazol administration acts via an induced release of these antigens, whose presence correlates with the degree of the inflammatory alleviation obtained. We thus provide evidence that the inflammatory state of the disease appears to be associated with soluble HLA levels because, 3 months after ceasing therapy, the circulating antigens in the serum return to the same levels that correspond to the pathological condition.

Three-year follow-up of [CA-125, CA 19-9, CA 15-3, SIL-2R, IL-6, IL-la, TNF-a, sCD8 and sCD4] levels in a woman with severe endometriosis.

A 37-year old woman presented with severe endometriosis and the patient underwent a conservative operation. We investigated the effect of treatment with danazol on the levels of CA-125, CA-19-9, CA 15-3, SIL-2R, IL-6, IL-1a, TNE-a, SCD8 and SCD4 in this woman. Our findings suggest that severe endometriosis is a condition which induces a rise of tumor markers and cytokine levels that are suppressed on danazol treatment.

Continuous spinal anesthesia/analgesia for perioperative management of morbidly obese patients undergoing laparotomy for gastroplastic surgery.

BACKGROUND: The authors determined prospectively the safety of continuous spinal anesthesia combined with general anesthesia and the efficacy of postoperative pain relief with continuous spinal analgesia for morbidly obese patients undergoing vertical banded gastroplasty. METHODS: 27 patients (13 men, 14 women) with a mean body mass index (BMI) of 50.4 +/- 7.8 and several co-morbidities were studied. All patients were anesthetized with the same anesthetic regimen, which included midazolam, fentanyl, propofol, muscle relaxants, nitrous oxide, isoflurane and intrathecal bupivacaine. Postoperative pain relief was provided for 5 days and all patients received the same regimen, which included intrathecal bupivacaine, fentanyl and intravenous tenoxicam. The intrathecal analgesic regimen was administered continuously through a pump which had the facility of providing bolus doses when requested in predetermined lockout intervals. Intra-operative monitoring included hemodynamic and respiratory parameters. Additional postoperative monitoring included respiratory rate, degree of sedation, sensory level of anesthesia, motor response and intensity of pain. RESULTS: Intraoperative anesthetic technique was safe and provided satisfactory results in the immediate postoperative period. Furthermore, the postoperative analgesia regimen provided effective analgesia in all patients. The mean doses of fentanyl and bupivacaine infused intrathecally for the first 24 postoperative hours were 14.1 +/- 2.0 microg.h(1) and 0.7 +/- 0.1 mg.h(1) respectively, while the requirements of analgesia decreased progressively with time. The technique provided effective analgesia with low pain scores, which was reflected by ease in mobilizing and performing physical exercises with the physiotherapist. Only minor complications related to anesthesia and analgesia were encountered. CONCLUSION: To our knowledge, this technique of anesthesia and postoperative analgesia has not been described before in morbidly obese patients. This regimen merits further controlled trials to establish its place in the perioperative management of morbidly obese patients.

Increase in serum leptin concentrations among women with endometriosis during danazol and leuprolide depot treatments.

OBJECTIVE: This study was undertaken to evaluate serum leptin concentrations in women with endometriosis during treatment with danazol and with leuprolide depot. STUDY DESIGN: Twenty patients aged 18 to 42 years with regular menses and documented pelvic endometriosis were recruited from a university hospital setting. Treatment was 200 mg danazol 3 times daily for 6 months or 3.75 mg leuprolide depot every 28 days for 6 months. Serum leptin concentrations were measured before, during, and after treatment. A single blood sample was taken from each of 10 control women without endometriosis for comparison. Serum leptin level was measured with a radioimmunoassay kit with human leptin, and analysis of variance and paired t tests were used for statistical analysis. RESULTS: Serum leptin levels were almost the same among women with endometriosis as in the control group. Leptin levels were higher among women with endometriosis during treatment with danazol and leuprolide(P <.001). Three months after treatment, leptin values remained moderately higher than before treatment. CONCLUSION: Danazol and leuprolide increased serum leptin levels. The mechanism of leptin increase is unclear. Further studies are needed to determine whether an adipogonadal axis exists.

A randomized comparison of danazol and leuprolide acetate suppression of serum-soluble CD23 levels in endometriosis.

OBJECTIVE: To determine the effects of treatment with danazol and leuprolide acetate depot on serum-soluble CD23 concentrations in women with endometriosis. METHODS: This randomized trial involved 20 women 18-42 years old with regular menses and known pelvic endometriosis who were recruited from a university hospital between 1993 and 1998. Ten women took 200 mg of danazol three times daily for 6 months, and the remaining ten were given 3.75 mg of leuprolide acetate depot every 28 days for 6 months. Blood-soluble CD23 levels were measured before treatment, during the last 15 days of the 6-month treatment course, and 3 months after treatment. Only one blood sample was taken from ten women without endometriosis, between the 5th and 7th days of their menstrual cycles. For statistical analysis, we used independent and paired t tests with the Pearson correlation coefficient. RESULTS: Soluble CD23 levels were significantly higher in women with endometriosis before treatment than in ten normal controls. Levels decreased significantly during treatment with either danazol or leuprolide acetate. Three months after treatment, soluble CD23 values remained lower than before treatment. There was no correlation between soluble CD23 concentrations and severity of endometriosis. CONCLUSION: Our findings suggest that endometriosis increases soluble CD23 levels, which can be suppressed with either danazol or leuprolide acetate injection.

Factors that may predispose to rupture of tubal ectopic pregnancy.

OBJECTIVE: The purpose of our study was to evaluate factors that may predispose to rupture of tubal ectopic pregnancy. The study included 99 cases of ectopic pregnancies that were treated during the 5-year period 1992-1996. RESULTS: It was found that: (1) tubal rupture is encountered more often in women with no history of ectopic pregnancy and in those who have full-term pregnancy, suggesting that ectopic pregnancy is less suspected in these women; (2) tubal rupture is encountered less often in lower age ectopic pregnancy; and (3) serum beta-hCG level does not predict tubal rupture. CONCLUSIONS: Rupture of the tube is more often observed in women with a history of ectopic pregnancy and in women with full-term pregnancy. Such observations suggest that ectopic pregnancy is less suspect in these cases.

Serum soluble CD23 and TNF-alpha in women with spontaneous abortion in the first trimester.

The present study was designed to investigate the participation of sCD23 and TNF-alpha in pregnant women in the first trimester. One hundred and forty-one patients were enrolled in the study. Women were classified into two groups. Serum sCD23 and TNF-alpha were measured in 73 normal pregnant women in the first trimester (Group I) and in 68 women with spontaneous abortion (Group II). We found that the mean values of TNF-alpha levels were higher in women with normal pregnancy than in women with spontaneous abortion (p < 0.05), whereas sCD23 levels of women in group II did not differ statistically from the controls. These results sustain the opinion that women with spontaneous abortion seem to have reduced TNF-alpha levels. However, determination of these immunological parameters provides no useful clinical information about disease activity and management.

Unexpected increase of the CA 19-9 tumour marker in patients with endometriosis.

The purpose of this study was to investigate whether the ovarian function of women with endometriosis could be identified by serologic concentration of the oncofetal antigen CA 19-9 before, during and after treatment for 6 months with danazol. A total of 15 women with endometriosis, 20-40 years old, were studied. The serum CA 19-9 antigen was measured by immunoradiometric assay. The measurement of CA 19-9 was repeated during the last 15 days of a 6-month therapy period with danazol and after 3 months from the end of the therapy in only seven women. It was found that: 1) Eight out of 15 women (53.3%) showed higher CA 19-9 values than the upper normal limit. 2) Danazol caused a significant decrease in the antigen values which remained stable after the cessation of therapy. This data suggests that endometriosis should be classified among other diseases which cause an increase in the serum levels of CA 19-9 and that ovarian function is related to antigen levels.

Delayed interval delivery and survival of the two fetuses after second trimester loss of one triplet.

Due to the implementation of assisted reproduction techniques, the incidence of multiple pregnancies associated with fetal and neonatal complications has significantly increased. A woman in the 24th week of a triplet pregnancy came to the hospital because of premature rupture of membranes of one amniotic sack and she had a miscarriage of one of the fetuses the same day. After confirmation of the viability of the two fetuses, she was kept under observation with antibiotic therapy only. The woman gave live birth to these remaining fetuses in her 32nd week of pregnancy. The outcome of this case demonstrates that watchful expectancy may be a feasible alternative to invasive intervention. The aim of this report is to add to the currently very limited literature of an expectant (conservative) policy with regard to pregnancy outcome after the early loss of a fetus from a multiple pregnancy.

Immunologic variables in normal pregnancy and spontaneous abortion.

OBJECTIVE: The aim of the study was to establish if pregnancy belongs to pathological situations, if it changes SIL-2R, sCD4 and sCD8 levels, and to verify if these levels have a prognostic value in the evaluation of pregnancy. PATIENTS AND METHODS: Thirty pregnant women in the first trimester of pregnancy were studied. Ten of them had a normal evolution of pregnancy, ten had a threatened abortion with a bad outcome, and ten had an ectopic pregnancy. We determined SIL-2R, sCD4, and sCD8 levels in the serum and in the amniotic fluid in 10 pregnant women in their second trimester, and in 10 healthy women without pregnancy (control group). RESULTS: We found that (a) 50% of the pregnant women in their first trimester had abnormal SIL-2R values, and 90% had abnormal sCD8 values; (b) 9/10 women with threatened abortion and bad outcome had abnormal SIL-2R values; (c) SIL-2R levels were significantly higher in the amniotic fluid than in the serum (P <.001). CONCLUSION: Our results sustain the opinion that pregnancy must be included among those situations that increase SIL-2R, sCD4, and sCD8 levels. SIL-2R levels greater than 1,300 U/mL carried a bad prognosis in the evolution of pregnancy.

Cytokine levels in seminal plasma.

We have studied IL-2, SIL-2R, and sCD4 concentrations in the seminal plasma of 20 healthy men (controls), 20 oligozoospermics and 20 azoospermics by the "sandwich" enzyme immunoassay technique. We have also measured IL-2, SIL-2R and sCD4 in the two fractions of the split ejaculate of 10 healthy men. Our results show that the mean IL-2 and sCD4 concentrations in the seminal plasma were significantly higher compared to the levels in the serum of normal men; furthermore, there were no significant differences of SIL-2R and sCD4 between the group of normal men and the groups of men with oligozoospermia or azoospermia. On the contrary, significantly higher levels of IL-2 and sCD4 were found in the first compared to the second fraction of the split ejaculates. Our results support the view that the estimation of IL-2 in seminal plasma has value concerning the quality of semen. On the contrary, the estimation of SIL-2R and sCD4 in seminal plasma are valueless concerning normal or abnormal semen. Finally, the prostate seems to be the main site or origin of IL-2 and sCD4.

Pseudo-Meigs' syndrome caused by paraovarian fibroma.

Meigs' syndrome includes an ovarian tumor, usually fibroma, associated with hydrothorax and ascites. It is accepted that uterine tumors, like fibromas, can also be associated with ascites and hydrothorax, but this is extremely rare. The mechanism of formation of peritoneal and pleural effusion is not well documented. The most likely pathogenesis ascribes the fluid formation to the filtration of interstitial fluid in the peritoneal through the tumor capsule, and the diffusion to the pleural space through the diaphragm lymphatic vessels at the foramen of Bochdalek. Paraovarian fibromas are also extremely rare neoplasms, probably of paramesonephric origin. It has been hypothesised that they can develop by proliferation of connective tissue cells around the Wolfian remnants. In this article, probably for the first time, a case of paraovarian fibroma with ascites and hydrothorax is presented.

Changes in immunologic variables (TNF-a, sCD8 and sCD4) during danazol treatment in patients with endometriosis.

DESIGN: The levels of TNF-a, sCD8, and sCD4 were measured in serum samples taken from 20 women. Blood samples for TNF-a, sCD8 and sCD4 levels were taken from 10 endometriotic women before treatment, during the last 15 days of a 6-month administration of danazol and 3 months after treatment. Blood samples were taken only once from 10 women without endometriosis (control group). RESULTS: TNF-a levels were higher in women with endometriosis before treatment compared to controls (P < .05). Administration of the drug significantly reduced the levels of TNF-a (P < .01) and sCD8 (P < .001). CONCLUSION: This study indicates that danazol significantly reduces endometriosis-associated autoimmune abnormalities.

Decreased sensitivity to insulin during treatment with danazol in women with endometriosis.

The aim of this study was to verify to what extent danazol alters insulin sensitivity. To this end, insulin tests were performed before the application of danazol and during the last 15 days of a six-month treatment with this agent on nine women, from 21 to 37 years of age, who had endometriosis. The same test was also performed on nine healthy women, 21 to 35 years of age, in whom laparoscopy did not reveal endometriosis or other pelvic pathology. It was found that the total response of glucose to insulin was significantly lower in women with endometriosis during treatment with danazol than it was in the same women before the application of this agent or in normal women too. Our results support the view that danazol induces resistance to insulin.